Acute and chronic end-stage lung diseases (ESLD) are increasing healthcare problems. Currently, when mechanical ventilation fails only extracorporeal membrane oxygenation (ECMO) with components designed and qualified for a few hours is available. Current ECMO systems are often associated with serious complications and generally are restricted to bedside use. A wearable, biocompatible integrated pump-lung would offer significant advantages to patients over existing options. Such a device would pose a prolonged ambulatory platform for natural lung healing from acute injury, a bridge to transplant or destination therapy, or for novel lung regenerative therapies. With support from the NHLBI, we have made remarkable progress in development of a wearable artificial pump-lung system (APLS) for ambulatory respiratory support. The goal of this renewal application is to develop a new class of gas exchange device with adaptive physiologic control for a wearable artificial lung system. We propose to develop unique strategies to reduce the sizes of gas exchanger devices and associated drive consoles and to provide adaptive respiratory support to ambulating ECMO patients. Three specific aims of the proposal are: (1) to develop a small-sized and multifunctional membrane respiratory assist device (MRAD) for ECMO therapy in the ambulatory setting. The novel MRAD will include a dual chamber gas exchanger (DCGE) for blood and gas flows with an integrated centrifugal pump; (2) to develop a lightweight console for the MRAD with auto-adaptive control based on the gas exchange demand of an ambulating patient. The portable console will be less than 20 lbs and can be placed into a backpack; and (3) to conduct in-vitro regulatory qualification tests and chronic (30-day) in-vivo animal experiments to assess the long-term function, biocompatibility, and durability of the MRAD and its biologic effect on the animal. The efficiency of the new gas exchange device will reduce its size and its console by near 30%. The reduced console size and weight will reduce its burden to the user and will permit its configuration into a backpack design as well as a small roller case. Completion of aims will redefine the technology appropriate for broadened use of ambulatory ECMO and for its out-of-hospital use.